Immunity can generally be classified as innate immunity or as adaptive immunity. Innate immune responses typically occur immediately upon infection to provide an early barrier to infectious disease whereas adaptive immune responses occur later with the generation of antigen-specific effector cells and often long term protective immunity. Innate immune responses do not generate lasting protective immunity but appear to play a role in the generation of the later arising adaptive immune response.
Toll-like receptors (TLRs) are essential for innate immune responses as they recognize several different antigens and initiate immunological/inflammatory responses such as cytokine production, and dendritic cell and macrophage activation. Especially, TLR2, TLR3, TLR4, TLR7, TLR8, and TLR9 recognize viral or bacterial ligands such as glycoprotein, single- or double-stranded RNA and polynucleotide containing unmethylated 5′-CG-3′ sequences. Immunostimulatory nucleic acid molecules stimulate the immune response through interaction with and signaling through the mammalian TLR9 receptor. See Hemmi et al. (2002) Nat. Immunol. 3:196-200. Mammalian DNA does not generally possess immunostimulatory activity due apparently to a low frequency of CG sequences and to most of the CG sequences having a methylated cytosine. Mammalian immune system cells thus appear to distinguish bacterial DNA from self DNA through the TLR9 receptor. TLR7 in contrast, is one of the main receptors sensing viral infection by recognizing uridine-rich single-stranded RNA.
The triggering of TLR7 and TLR9 in plasmacytoid dendritic cells precursors (PDC) and B cells by self nucleic acids is key in the pathogenesis of Systemic Lupus Erythematosus (SLE). This leads to the production of type I IFNs from PDC that can be detected by the upregulation of IFN-regulated genes in the blood of patients (IFN-signature) and anti-DNA and anti-RNP antibodies from B cells that form immune complexes (IC) with DNA or RNA from dying cells (Barrat and Coffman, 2008; Marshak-Rothstein, 2006). PDC are the major source of IFN-α induced by nucleic acid-containing ICs. Once activated by self DNA/chromatin or snRNP-containing IC, PDCs migrate from the blood into inflamed tissues including skin and kidney.
IFN-α and PDC have been proposed to contribute to the pathogenesis of other autoimmune diseases characterized by IFN-α signature as well. Indeed, Type I IFN-producing PDC accumulate in the pancreas, muscle and salivary glands of people affected by diabetes mellitus, dermatomyositis and Sjögren's syndrome respectively, strongly suggesting that dysregulated PDC activation could be a more general feature of autoimmune disease (Barrat and Coffman, 2008; Guiducci et al., 2009; Ueno et al., 2007).
SLE patients are often treated with strong immunosuppressive regimens, including cytotoxic drugs, antimalarial compounds and glucocorticoids (GC). Glucocorticoids have strong anti-inflammatory effects on both acquired and innate immune functions. They inhibit B and T cell responses and effector functions of monocytes and neutrophils. At the cellular level, GC inhibit NF-kB activity, thought to be the main mechanism by which GC exert their anti-inflammatory effects. In lupus, GC are typically administered orally on a daily basis, as the typical every other day regimens cannot maintain disease control. When doses greater than 40 mg/day are required, patients receive intravenous methylprednisolone (Solumedrol) pulse therapy (e.g., doses up to 30 mg/kg/day or 1 g/day given each day for 3 days). Such treatment can transiently reduce disease activity, but often does not induce remission or prevent end organ damage. The reason why treatment of SLE requires much higher GC doses than many other autoimmune diseases is not clear.